tbuckley/cabot-search huggingface dataset:
Racial impact (Asian vs. White) on the prognosis of patients with de novo mCSPC: An analysis on LATITUDE, SEER and NCDB.
Authors: Xudong Ni, Michael Luu, Weiwei Ma, Stephen J. Freedland, Timothy Daskivich, Zhu Yao
Journal: Journal of Clinical Oncology (2023)

27 Background: Little is known about the impact of race (Asian or White) on the long-term survival outcomes of men with de novo mCSPC treated with different methods. Understanding racial disparities in survival is critical for accurate prognostic risk stratification and for informing the design of multiregional clinical trials. Methods: This multiple-cohort study included individual patient-level data of men with de novo mCSPC from the following 3 cohorts: LATITUDE clinical trial data (LATITUDE [n=1199]); Surveillance, Epidemiology, and End Results (SEER [n=5496]); and the National Cancer Database (NCDB [n=10366]). Key efficacy outcomes were overall survival (OS) in LATTITUDE and NCDB as well as OS and cancer-specific survival (CSS) in SEER. Kaplan-Meier analysis with propensity score matching (PSM) was used for survival analysis. Hazard ratios were calculated using a multivariate Cox proportional-hazard model. Results: Across all three cohorts, Asian patients diagnosed with de novo mCSPC had better OS and CSS than White patients. In LATITUDE, median OS was significantly longer in Asian than in White men in the ADT+Abiraterone+Prednisone group (not reached vs. 43.8 months, HR 0.47, 95%CI 0.28–0.77, P=0.003 for Cox analysis) as well as in the ADT+placebo group (57.6 months vs. 32.7 months, HR 0.49, 95%CI 0.32–0.75, P=0.001 for cox analysis). In SEER, among all patients diagnosed with de novo mCSPC, median OS was significantly longer in Asian than in White men (53 months vs. 42 months, HR 0.76, 95%CI 0.68–0.85, P&lt;0.001 for Cox analysis). When analyses were restricted to patients who received chemotherapy, Asian men again had longer OS (67 months vs. 41 months, HR 0.70 95% CI 0.51–0.95, P=0.02 for Cox analysis). Using CSS data in SEER resulted in similar conclusions as OS. In NCDB, Asians also had longer OS than White men (whole cohort: 38 months vs. 26 months, HR 0.73, 95%CI 0.63–0.84, P=0.02 for Cox analysis; ADT subgroup: 41 months vs. 26 months, HR 0.75, 95%CI 0.63–0.89, P&lt;0.001 for Cox analysis; Chemotherapy subgroup: 34 months vs. 27 months, HR 0.80, 95%CI 0.69–0.94, P=0.005 for Cox analysis). Conclusions: Asian men had better OS and CSS than White men with mCSPC across different treatment regimens in all datasets examined and should be considered as an independent prognostic factor. This racial difference should also be considered when designing multiregional clinical trials. Further studies including biological analyses are needed to understand the etiology of the apparent survival advantage for Asian men. [Table: see text]
The genomic landscape of <i>TERT</i> alterations in bladder cancer.
Authors: Aimee Jalkanen, Gargi D. Basu, David W. Hall, Jess R Hoag, Janine R. LoBello, Frederick L. Baehner, Snehal Govind Thakkar, Tanya B. Dorff
Journal: Journal of Clinical Oncology (2023)

551 Background: Some of the most common mutations seen across cancers occur in TERT, where promoter mutations upregulate TERT transcription. In bladder cancer, TERT mutations are associated with poor prognosis, especially for recurrence. In this study, we identified TERT promoter mutations in bladder cancer and determined whether mutations at other genes were significantly associated. We also examined whether TERT mutation frequency is associated with age or gender. Methods: We utilized the Oncomap ExTra genomic profiling assay to identify alterations. This assay performs tumor-normal, whole-exome, whole-transcriptome DNA and RNA sequencing to identify somatic alterations. In addition to the exome, several noncoding regions are sequenced, including the TERT promoter. Single-nucleotide variants, indels, copy number alterations, alternative transcripts, and gene fusions are all detected. Tumor mutational burden (TMB) and microsatellite instability (MSI) are also calculated. Results: Of 194 bladder cancer patient specimens assayed between April 2018 and August 2022, 153 (78.9%) carried a TERT promotor mutation (Table). The C228T and C250T single base substitutions were the most common, at 57.7% and 15.5%, respectively. Of note, one patient had a TERT fusion caused by an inversion involving MARCHF6 as the partner gene. Many patients harbored mutations in other genes, with two possibly associated with TERT status: BRCA2 was mutated in 6 (3.9%) TERT-mutated and 7 (17.1%) TERT-wild type patients (Fisher’s Exact Test, p=0.007), and FGFR3 was mutated in 33 (21.6%) TERT-mutated and 3 (7.3%) TERT-wild type patients (p=0.042). In addition, TMB-high was in 93 (60.8%) TERT-mutated and 10 (24.4%) TERT-wild type patients (p=0.071). None of these associations were significant after correcting for the false discovery rate. There was no significant difference in median (or average) age of individuals with versus without a TERT mutation (71.0 and 70.0 yrs, respectively). In addition, there was no significant difference in frequency of TERT alterations in males (82.0%) versus females (70.9%). Conclusions: The Oncomap ExTra assay allowed identification of both commonly observed and rare TERT promoter mutations, including a fusion, in 78.9% of bladder cancer patients. Such assays are useful to identify both TERT alterations prognostic for progression and patients eligible for clinical trials evaluating TERT-directed therapies. In addition, TERT mutations may be associated with FGFR3 mutations and high TMB, which have matched therapies, though these associations need to be validated in an independent cohort. [Table: see text]
Real-world assessment of AR-LBD mutations in metastatic castration-resistant prostate cancer.
Authors: Emmanuel S. Antonarakis, Nicole Zhang, Jayati Saha, Liina Nevalaita, Scott A. Shell, Chris Garratt, Tarja Ikonen, Karim Fizazi
Journal: Journal of Clinical Oncology (2023)

204 Background: Treatment of men with metastatic castration-resistant prostate cancer (mCRPC) using drugs targeting the AR pathway is hampered by development of resistance including activating AR ligand-binding domain (LBD) point mutations. AR LBD mutations are found in approximately 10-20% of patients (pts) with mCRPC progressing on AR pathway inhibition (ARPi) therapy and may be associated with AR activation by alternative steroid hormones. We utilized the Guardant INFORM real-world database to explore the detection rate and clinical features associated with AR-LBD mutations in men with mCRPC. Methods: This observational study was conducted in a nationally representative clinical-genomic database of 200,000+ advanced cancer pts undergoing comprehensive ctDNA analysis (Guardant360, Redwood City, CA) between 2014 and 2021, with associated clinical information from administrative claims. ctDNA samples of men with mCRPC were assessed for presence or absence of an activating AR-LBD mutation. The incidence of co-occurring genetic alterations was also investigated. Clinical outcomes were studied for matched cohorts comparing pts following first line (1L) or second line (2L) mCRPC therapy with or without AR-LBD mutations. Results: Of 15,705 prostate cancer pts included in the database, 8420 (53.6%) had mCRPC at the time of sample collection. 4122 (49.0%) of these mCRPC pts had prior treatment with an ARPi, of which 854 (21%) had an AR-LBD mutation. AR-LBD mutation prevalence was 15% in mCRPC pts untreated with an ARPi, 23% in those after 1 line, and 24% in those after 2 lines of ARPi treatment. AR L702H and T878A/S showed the greatest increase in prevalence post abiraterone, whereas AR L702H, T878S and F877L had the greatest increase in prevalence post enzalutamide. Prevalence of AR L702H and H875Y doubled (from 8.8% to 17.5%) for pts that received chemotherapy post ARPi, while AR F877L incidence declined by half (3.5% to 1.7%). Compared to pts without AR-LBD mutations, AR-LBD+ mCRPC pts were enriched for co-alterations in APC, CTNNB1, PTEN, BRCA2, and ARID1A. Rates of TP53 and RB1 alterations were comparable in the AR-LBD+ and ARLBD- cohorts. Matched mCRPC pts had similar time-to-treatment-discontinuation (TTD) and time-to-next-treatment (TTNT) between AR-LBD+ and AR-LBD- mCRPC pts in the 1L and 2L settings; however, AR-LBD+ pts exhibited worse overall survival from 1L mCRPC therapy (50.1 vs 60.7 months, log-rank P=0.013). Conclusions: In this large database, the overall detection rate of activating AR-LBD mutations in men with mCRPC undergoing ctDNA analysis was 21%, and increased with prior use of 2 nd generation ARPi (abiraterone and enzalutamide). Men with AR-LBD mutations were more likely to harbor other alterations relevant to tumor progression. These findings inform on the ctDNA prevalence and impact of AR-LBD mutations in a real-world dataset of mCRPC.
Additional biological and clinical characteristics to refine International Metastatic RCC Database Consortium (IMDC) prognostic/predictive assessment in metastatic renal cell carcinoma (mRCC).
Authors: Ilaria Zampiva, Sara Merler, Nicola Inzerilli, Francesca Zacchi, Stefano Manduca, Sarah Pafumi, Michela Piacentini, Stefano Marletta, Ursula Cesta Incani, Lorena Torroni, Roberta Vesentini, Pierpaolo Marchetti, Emanuela Fantinel, Andrea Zivi, Anna Caliò, Matteo Brunelli, Giuseppe Verlato, Michele Milella
Journal: Journal of Clinical Oncology (2023)

705 Background: mRCC prognostic stratification is currently based on the IMDC score. However, some patients experience outcomes markedly different from those predicted by the median outcome of their risk class. Moreover, risk scores are prognostic, rather than predictive, and developing reproducible, affordable, biology-based predictive biomarkers to tailor treatment choices in individual pts remains an unmet clinical need. Methods: A retrospective cohort of 113 mRCC pts treated at the Verona University Hospital Trust between 2013 and 2021 was explored to identify additional clinical prognostic factors for OS to complement IMDC score. Outlier pts (i.e. individual pts whose clinical outcome differed significantly from the median of the IMDC group they belonged to) were further explored to find putative molecular signatures, using FISH and IHC assays. Results: At a median follow-up of 69 months (range 18-136m), novel variables impacting on OS in addition to IMDC risk group were identified: bone, central nervous system (CNS) and pancreatic mets and high neutrophil/lymphocyte ratio (N/L) with a cut-off of 3.2. We also analyzed outliers: 3 good-risk pts with lower than expected OS, 4 poor-risk pts with longer than expected OS, and two intermediate-risk pts with long treatment response. Two putative signatures were found predictive of disease behavior: a cold signature (9p loss, poor of TILs) and a hot signature (rich in CD56+, CD15+ and CD8+ infiltrating cells). The cold and hot signatures were found in good risk pts with bad OS and poor-risk pts good OS, respectively; both intermediate-risk pts had a hot signature, consistent with their disease course. Conclusions: Additional clinical and molecular factors have been identified to possibly improve IMDC prognostic performance; multivariable models including them along with standard IMDC are being developed. Molecular analysis suggests potential signatures to be applied in routine clinical practice, whose predictive performance could be validated in prospective multicentric trials. [Table: see text]
Burden of surgeries and surgical complications in patients with Von Hippel Lindau (VHL) disease before and after treatment with belzutifan.
Authors: Lin Wang, Arielle G. Bensimon, Murali Sundaram, Ruifeng Xu, Yizhen Lai, Yanfang Liu, Shahrul Mt-Isa, Danni Yang, Jonathan Freimark, Yan Song, Eric Jonasch
Journal: Journal of Clinical Oncology (2023)

733 Background: VHL disease is a rare hereditary condition that causes abnormal tumor growth in multiple organs, including renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas (Hb), pancreatic neuroendocrine tumors (pNET), and other tumors. Repeated surgeries are often required due to ongoing tumor recurrences and can lead to complications such as chronic kidney disease, pancreatic insufficiency, and neurological deficit. Belzutifan is a hypoxia-inducible factor inhibitor approved in the US for the treatment of VHL-associated RCC, CNS Hb, or pNET not requiring immediate surgery. This study aimed to quantify the annual rate and costs of VHL-related surgeries and surgical complications before and after belzutifan initiation. Methods: Surgeries were observed during the periods before and after belzutifan initiation in the single-arm phase 2 LITESPARK-004 trial (NCT03401788) among adults with VHL-RCC. Rates of RCC surgeries were obtained by fitting exponential survival models to: time from treatment initiation to the next renal surgery; and time (looking backward) from treatment initiation to the most recent renal surgery before treatment. Rates of surgeries related to other VHL manifestations were calculated as number of surgeries divided by person-years at risk, using all available post-treatment follow up (151 person-years; median [range] per patient: 29.2 [4.2-37.5] months) and equivalent person-years in the pre-treatment period. Complication risks per surgery and unit costs of surgeries and complications were obtained from a retrospective study on VHL within the Optum Clinformatics Data Mart (2000-2020). Annual per-patient costs of surgeries and complications were estimated in 2020 US dollars over the pre- and post-treatment periods from a US third-party payer perspective. Results: Among trial participants (N=61), the rate of RCC surgeries (surgeries/person-year) decreased 87% (0.108 to 0.014) after belzutifan initiation. The rate of other surgeries decreased 98% (0.265 to 0.007), with CNS Hb surgeries decreasing from 0.185 to 0.007, pNET surgeries from 0.013 to 0, adrenal lesion surgeries from 0.007 to 0, and retinal Hb surgeries from 0.060 to 0. Belzutifan was accordingly estimated to reduce per-patient average annual costs of surgeries and complications from $57,259 to $2,536. Conclusions: Healthcare costs of surgeries and surgical complications are substantial among patients with VHL-RCC. In a trial-based cost-consequence analysis, belzutifan was estimated to decrease annual surgery and complication costs by 96%, based on observed reductions in VHL-related surgeries. [Table: see text]
First UK experience of apalutamide in metastatic and non-metastatic prostate cancer outside of clinical trials.
Authors: Prantik Das, Rania Mohammed, Naveed Sarwar, Omar Din, Ankit Jain, Jessica Davies, Thangrarajh Mugunthan, Ajith Nair, Aruni Ghose, Seheli Bandyopadhyay, Roopesh Krishnappa, Pooja Iyer, Lauren Jones, Nikhil Vasdev, Maja Moldawa, Rebecca Devine, Robert Hughes, Anand Sharma
Journal: Journal of Clinical Oncology (2023)

106 Background: Apalutamide plus androgen deprivation therapy(ADT) has been approved as a treatment option for castrate resistant non metastatic prostate cancer (nmCRPC) with a high risk of developing metastatic disease. It has also demonstrated benefit in patients with metastatic, castration-sensitive prostate (mHSPC) cancer, with improvement in overall and radiographic progression–free survival. Here we report our first experience of using Apalutamide in real life clinical practice. Methods: A cohort of 108 patients from 5 UK centres were included, among them 68 were metastatic and 40 non metastatic. All patients were treated with Apalutamide 240 mg along with ADT until disease progression. The primary endpoint was objective rate (ORR) and secondary endpoints included treatment duration and safety. Results: The median age for the whole cohort was 71 years (interquartile range 43-91), 73 years for nmCRPC and 69 years for mHSPC respectively. 81% had biopsy proven malignancy. A total of 11.7% with mHSPC had received prior radical treatment (prostatectomy or radiotherapy for localised disease), compared to 92.5% patients in the non-metastatic cohort. PSA reached undetectable levels (&lt;0.04 ng per ml) in 67% of the patients in the metastatic and 60% in non-metastatic subset respectively. In patients with mHSPC, who had radiological assessments performed, the response rates at 6 months were as follows: partial response (24%), stable disease (74%) and progressive disease (4%).39% of the whole cohort, reported grade 2 and above toxicities. The commonest were skin rash, thyroid dysfunction, hypertension, lethargy and hot flushes. Adverse events led to discontinuation in 1 patient and dose reduction in 1 patient. Conclusions: Our experience of using Apalutamide has shown good biochemical and radiological response in both nmCRPC and mHSPC. Treatment was well tolerated with low rates of treatment discontinuation. Further follow up of these patients will guide us in terms of overall survival.
Outcomes with immune checkpoint inhibitor (ICI) therapy in patients with FGFR2/3 alterations in advanced urothelial carcinoma (aUC).
Authors: Rafee Talukder, Dimitra Rafailia Bakaloudi, Dimitrios Makrakis, Nishita Tripathi, Neeraj Agarwal, Tanya Jindal, Vadim S Koshkin, Jeffrey Johnson, Yousef Zakharia, Jason Brown, Macarena Rey-Cárdenas, Daniel Castellano, Ajjai Shivaram Alva, Roubini Zakopoulou, James Korolewicz, Alexandra Drakaki, Pedro C. Barata, Petros Grivas, Ali Raza Khaki
Journal: Journal of Clinical Oncology (2023)

478 Background: Erdafitinib is FDA-approved for patients (pts) with advanced urothelial carcinoma (aUC) with FGFR2/3 mutation or fusion and progression after platinum-based chemotherapy. It is postulated that FGFR3-altered aUC may be a “cold tumor” and associated with non-T cell-inflamed phenotype and, thus, may be less responsive to ICI. We hypothesized that pts with aUC that harbor FGFR2/3 alterations would have lower response and shorter survival on ICI. Methods: We performed a retrospective cohort study of pts with aUC treated with ICI and available genomic data in 11 institutions; pts with pure non-UC, treated with combinations or on clinical trial were excluded. Outcomes (overall response rate [ORR], progression free survival [PFS] and overall survival [OS] were compared in pts with and without FGFR2/3 alterations. PFS and OS was compared using Cox proportional hazards. All analyses were performed in the overall population and also categorized by treatment line (1 st line [1L] vs salvage [2+L]). Multivariable models were adjusted for an internally developed risk score for 1L and Bellmunt risk score for 2+L; p&lt;0.05 was significant. Results: 310 pts met inclusion criteria; 217 pts, 206 pts, and 204 pts were included in ORR, OS and PFS analyses, respectively. Median follow up time was 37 months [mo]. Overall, median age at ICI initiation was 69, 74% men, 85% White, 27% mixed histology, 24% upper tract, 15% liver metastases, 55% ECOG PS 0-1; 101 pts (33% of total population) had FGFR2 or FGFR3 mutation/fusion. ORR to ICI in pts with FGFR2/3 alteration was 25% (95% CI 15-37%) vs 46% (95% CI 38-55%) in pts without such alterations. PFS was shorter for pts with FGFR2/3 alteration (median [m] PFS 4 mo vs 7 mo without such alterations; HR=1.53 [95% CI 1.09-2.15], p=0.015). However, OS was similar in both groups (mOS 14 mo in both groups; HR=1.09 [95% CI 0.75-1.58], p=0.65). ORR, PFS and OS analyses stratified by ICI treatment line (1L vs 2+L) are shown in the Table. Conclusions: In this multisite retrospective study, the presence of FGFR2/3 alterations was associated with lower ORR and shorter PFS in pts with aUC treated with ICI. Limitations include retrospective nature, lack of randomization and central scan review, selection bias, missing data, and possible residual confounding. Findings suggest that FGFR2/3 alterations may impact response and PFS with ICI and might inform discussion on the optimal sequence of therapies in aUC but need external validation and ideally clinical trial data. [Table: see text]
Comparison of serum miR-371a-3p assay performance by digital droplet PCR and reverse transcriptase quantitative PCR in patients with malignant germ cell tumor.
Authors: Michelle Nuno, John T. Lafin, Cinzia Scarpini, Anna Savelyeva, Zhaohui Wang, Jeffrey Gagan, Liwei Jia, Cheryl Lewis, Sarah Murray, Yun Cheng, Vitaly Margulis, Solomon L. Woldu, Douglas Strand, Nicholas Coleman, James F. Amatruda, Lindsay Lindsay Frazier, Matthew Murray, Aditya Bagrodia
Journal: Journal of Clinical Oncology (2023)

426 Background: MicroRNAs have shown promise as potential germ cell tumor (GCT) biomarkers. In particular, previous work has shown miR-371a-3p alone may serve as a biomarker for GCTs, demonstrating higher sensitivity than current biomarkers. Quantitative reverse transcriptase PCR (RT-qPCR) has been commonly used to measure circulating levels of miR-371a-3p. More recently, miR-371a-3p has also been measured using digital droplet PCR (ddPCR), which has the potential advantage of absolute quantification. Here, we compared the performance of miR-371a-3p as quantified by RT-qPCR and ddPCR. Methods: Patient samples from the University of Texas Southwestern (UTSW) Medical Center and the University of Cambridge (UoC) were evaluated using both RT-qPCR and ddPCR, as per current protocols (RT-qPCR) or as per standard manufacturer’s recommendations (ddPCR). A range of clinical scenarios (pre-orchiectomy, chemotherapy-naïve RPLND) were intentionally selected. We compared the performance of the two assays using receiver operating characteristic (ROC) curves and area under the curve (AUC) values. We also determined an optimal threshold for each procedure by maximizing the Youden Index and compared the corresponding estimated sensitivity and specificity. Results: Data were available for 69 patients. Among these patients, 35 (50.7%) had malignant GCT (MGCT) and 34 (49.3%) had either non-MGCT (n=26) or no tumor (n=8). Patients with non-MGCT or with no tumor were considered controls. Cq values were generally lower among patients with MGCT and the number of positive droplets was higher compared with controls. The AUC was 0.96 when using RT-qPCR and 0.82 when using ddPCR to classify patients based on circulating miR-371a-3p. The optimal threshold for ddPCR was determined to be 17.5 positive droplets with a corresponding estimated sensitivity of 71% and 100% specificity. For RT-qPCR, the optimal threshold was determined to be Cq=28.52, with a corresponding estimated sensitivity of 83% and specificity of 100%. Conclusions: RT-qPCR was more sensitive in identifying MGCT patients in our current cohort when compared with ddPCR. Further investigations are required to optimize PCR methodology, particularly for ddPCR, and determine whether e.g., tumor volume and/or clinical context affects ddPCR performance. [Table: see text]